This invention relates to amide derivatives of 1,4-di-substituted piperidine antagonists for melanin-concentrating hormone (MCH) and their use in the treatment of obesity and diabetes.
MCH, a cyclic peptide, was first identified over a decade ago in teleost fish where it appears to regulate color change. More recently, MCH has been the subject of investigation for its possible role as a regulator of eating behavior in mammals. As reported by Shimada et al., Nature, Vol. 396 (Dec. 17, 1998), pp. 670-673, MCH-deficient mice have reduced body weight and leanness due to hypophagia (reduced feeding). In view of their findings, the authors have suggested that antagonists of MCH action may be effective for the treatment of obesity. U.S. Pat. No. 5,908,830 discloses a combination therapy for the treatment of diabetes or obesity involving the administration of a metabolic rate increasing agent and a feeding behavior modifying agent, an example of the latter being an MCH antagonist.
Piperidine-derivative muscarinic antagonists useful in the treatment of cognitive disorders such as Alzheimer""s disease are disclosed in U.S. Pat. No. 6,037,352. In particular, U.S. Pat. No. 6,037,352 discloses compounds of the generic formula 
wherein, inter alia, Y is CH; Z is N; X is xe2x80x94NHCOxe2x80x94; R is substituted benzyl or cycloalkylalkyl; R1, R21, R3, R4, R27 and R28 are each hydrogen; and R2 is optionally substituted cycloalkyl or arylalkyl. U.S. Pat. No. 6,037,352 does not disclose the use of the compounds for treating obesity or diabetes.
The present invention relates to compounds represented by structural formula I: 
or a pharmaceutically acceptable salt, ester or solvate thereof, wherein
W is R1xe2x80x94CR3R12NR4C(O)xe2x80x94 or R11C(O)NR4xe2x80x94;
the dotted line is an optional double bond;
X is xe2x80x94CHR8xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(xe2x95x90NOR9)xe2x80x94, or, when the double bond is present, xe2x80x94CR8xe2x95x90;
Y is 
xe2x80x83or, when the double bond is present, 
R1 is R5xe2x80x94(C3-C8)cycloalkyl, R5xe2x80x94(C3-C8)cycloalkyl(C1-C6)alkyl, R5-aryl, R5-aryl-(C1-C6)alkyl, R5-heteroaryl, R5-heteroaryl(C1-C6)alkyl, R5-heterocycloalkyl or R5-heterocycloalkyl(C1-C6)alkyl;
R2 is R6-aryl or R6-heteroaryl;
n is 1, 2 or 3;
R3 is C1-C6 alkyl, aryl or heteroaryl;
R4 is H or C1-C6 alkyl;
R5 is 1-4 substituents independently selected from the group consisting of H, C1-C6 alkyl, halogen, xe2x80x94OH, C1-C6 alkoxy, xe2x80x94CF3, (C1-C6)-alkoxycarbonyl, xe2x80x94SO2NHR4, xe2x80x94C(O)NHR4, xe2x80x94NR4C(O)NHR4, xe2x80x94NR4C(O)R4, xe2x80x94NR4SO2R4, R13-phenyl and naphthyl;
R6 is 1-4 substituents independently selected from the group consisting of H, C1-C6 alkyl, halogen, xe2x80x94OH, xe2x80x94SH, xe2x80x94S(C1-C6 alkyl), xe2x80x94CN, C1-C6 alkoxy, C1-C6 alkylcarboxy, CF3, xe2x80x94NO2, xe2x80x94NH2, (C1-C6)alkylamino, phenyl, (C1-C6)-alkoxycarbonyl and R7-phenoxy, or adjacent ring carbon atoms form a ring with the group xe2x80x94O(CH2)1-2Oxe2x80x94, xe2x80x94O(CH2)2-3xe2x80x94 or xe2x80x94O(CF2)Oxe2x80x94;
R7 is 1-3 substituents independently selected from the group consisting of H, C1-C6 alkyl, halogen, xe2x80x94OH, C1-C6 alkoxy and CF3;
R8 is H, C1-C6 alkyl or (C1-C4)alkoxy-(C1-C4)alkyl;
R9 is H, C1-C6 alkyl or aryl-(C1-C4)alkyl;
R10 is independently selected from the group consisting of H, C1-C6 alkyl and aryl;
R11 is 
or, when R2 is R6-heteroaryl or R10 is not H, R11 can also be R5-phenyl(C0-C2)alkyl;
m is 1, 2, 3, 4 or 5;
R12 is H or C1-C6 alkyl;
R13 is 1 to 3 substituents independently selected from the group consisting of H, C1-C6 alkyl, halogen, xe2x80x94OH, C1-C6 alkoxy, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2 and xe2x80x94C(O)CH3; and
R14 is 1-3 substituents independently selected from the group consisting of H, C1-C6 alkyl, halogen, xe2x80x94OH, C1-C6 alkoxy and CF3.
The present invention also relates to a method of treating eating disorders, such as obesity and hyperphagia, and diabetes comprising administering to a mammal in need of such treatment an effective amount of a compound of formula I.
Another aspect of the invention is a pharmaceutical composition for treating eating disorders and diabetes which comprises a compound of formula I in combination with a pharmaceutically acceptable carrier.
Referring to formula I, above, one group of preferred compounds is that wherein W is R1xe2x80x94CR3R12NR4C(O)xe2x80x94.
R1 is preferably R5-phenyl, R5 is preferably H, halogen, C1-C6 alkyl or phenyl, more preferably halogen or phenyl.
Another group of preferred compounds is that wherein R2 is R6-aryl, especially when n is 1. More preferred is R6-aryl wherein xe2x80x9carylxe2x80x9d is phenyl and R6 is 1-2 substituents.
X is preferably xe2x80x94CHR8 wherein R8 is H and Y is CH, or X and Y form a double bond.
R3 is preferably ethyl or methyl, and R4 and R12 are each preferably H.
R10 is preferably H or xe2x80x94CH3; when n is 2-5, preferably only one R10 is alkyl and the rest are hydrogen.
Except where stated otherwise, the following definitions apply throughout the present specification and claims. These definitions apply regardless of whether a term is used by itself or in combination with other terms. Hence the definition of xe2x80x9calkylxe2x80x9d applies to xe2x80x9calkylxe2x80x9d as well as to the xe2x80x9calkylxe2x80x9d portions of xe2x80x9calkoxyxe2x80x9d, etc.
xe2x80x9cAlkylxe2x80x9d represents a straight or branched saturated hydrocarbon chain having the designated number of carbon atoms. Where the number of carbon atoms is not specified, 1 to 6 carbons are intended.
xe2x80x9cCycloalkylxe2x80x9d represents a saturated carbocyclic ring having 3 to 8 carbon atoms.
The term xe2x80x9cheterocycloalkylxe2x80x9d refers to 4- to 7-membered saturated rings comprising 1 to 3 heteroatoms independently selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94NR7xe2x80x94, wherein R7 is H or C1-C6 alkyl, and wherein the remaining ring members are carbon. Where a heterocyclic ring comprises more than one heteroatom, no rings are formed where there are adjacent oxygen atoms, adjacent sulfur atoms, or three consecutive heteroatoms. Examples of heterocyclic rings are tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl.
Halogen represents fluoro, chloro, bromo or iodo.
Aryl represents a monoaromatic ring or a bicyclic fused ring system of 6- to 10 carbon atoms, possessing one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and the like.
Heteroaryl means a 5- to 10-membered single or benzofused aromatic ring comprising 1 to 3 heteroatoms independently selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94Nxe2x95x90, provided that the rings do not include adjacent oxygen and/or sulfur atoms. Examples of single ring heteroaryl groups are pyridyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, thiadiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazolyl. Examples of benzofused rings are indolyl, benzofuranyl, quinolyl, quinazolinyl, quinoxalinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, thianaphthenyl, and benzofurazanyl. N-oxides are also included. All positional isomers are contemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl.
When a variable appears more than once in the structural formula, for example R5, the identity of each variable appearing more than once may be independently selected from the definition for that variable.
N-oxides can form on a tertiary nitrogen present in an R1 or R2 substituent, or on xe2x95x90Nxe2x80x94 in a heteroaryl ring substituent and are included in the compounds of formula I.
For compounds of the invention having at least one asymmetrical carbon atom, all isomers, including diastereomers, enantiomers and rotational isomers are contemplated as being part of this invention. The invention includes d and l isomers in both pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers of a compound of formula I. The preferred stereochemistry for compounds of the invention wherein W is R1xe2x80x94CR3R12NR4C(O)xe2x80x94 is shown in formula IA: 
Compounds of formula I can exist in unsolvated and solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like, are equivalent to the unsolvated forms for purposes of this invention.
A compound of formula I may form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution, such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia or sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention.
Compounds of formula I can be produced by processes known to those skilled in the art using either solution phase or solid phase synthesis as shown in the following reaction schemes and in the preparations and examples below:
Compounds of Formula 1 wherein W is R1xe2x80x94CR3R12NR4C(O)xe2x80x94 can be produced as shown in Scheme 1. 
The synthesis of compounds such as 3 can be accomplished by the reaction of 9-borabicyclo[3.3.1]nonane (9-BBN) with an olefin such as 1 followed by the Suzuki coupling with an aryl halide such as 1a to afford compounds 2. Hydrolysis of ester 2 and subsequent deprotection of the N-Boc provides the amino acid intermediate which is protected by treatment with 9-fluorenylmethoxycarbonyl oxysuccinimide (FmocOSU). This product is then converted into the acid chloride 3 upon treatment with reagents such as POCl3 or oxalyl chloride.
The amine (R1CR12R3NR5H) is reacted with Argopore-MB-CHO resin (Argonaut Corporation, San Carlos, Calif.) by reductive alkylation with sodium triacetoxyborohydride. Subsequent acylation of the resin-bound amine with activated acids such as acid chlorides 3, deprotection of the N-Fmoc group, followed by reductive alkylation with aldehydes or ketones, or reaction with an aldehyde followed by treatment with a Grignard reagent, or by reaction with the appropriate mesylate or alkyl halide, provides a resin bound intermediate, which on treatment with trifluoroacetic acid (TFA) produces compounds of Formula I.
Compounds of Formula 1 wherein W is R11C(O)NR4 can be prepared according to Scheme 2. 
Compounds 10 can be prepared by the route shown in Scheme 2 by first converting an acid such as 4 into an amine such as 6 by the Curtius reaction, for example by treatment with diphenylphosphoryl azide in an alcohol such as t-butanol followed by hydrolysis. Subsequent reaction with a resin-bound aldehyde such as the Argopore MB-CHO resin under reducing conditions provides a resin-bound amine 7 which can be further functionalized by reaction with activated carboxylic acid derivatives such as acid chlorides. Removal of the FMOC group and reductive alkylation with carbonyl-containing compounds, followed by treatment with acid to remove the compound from the polymeric resin, provides compounds 10.
Alternatively, compounds of formula I are prepared as shown in Scheme 3 by reacting an aryl bromide such as 11a with an alkyl lithium reagent, followed by addition of an aryl isocyanate. Subsequent removal of the BOC group from compound 12 by treatment with acid and then introduction of the R2 group by alkylation or reductive alkylation provides compounds such as 13. Furthermore, 11 can also be elaborated into compounds such as 11i as shown in Scheme 3. 
Compounds wherein R10 is alkyl can be prepared by the following procedure: 
Additional compounds of formula I are prepared according the route shown in Scheme 5 (specific compounds are shown, but the procedure may be modified to make other compounds within the scope of formula I): 
Compounds of formula I wherein W is R1xe2x80x94CR3R12NR4C(O)xe2x80x94 and R1 is biphenyl can be prepared by the Suzuki coupling reaction: 
The iodophenyl analogs on Argopore-MB-CHO resin are treated with phenylboronic acid, K2CO3, Pd(dppf)Cl2 and 1-methyl-2-pyrrolidinone. The resin is washed, then cleaved using 10% TFA/CH2Cl2.
Starting materials are prepared by known methods and/or methods described in the Preparations.
The compounds of formula I exhibit MCH receptor antagonizing activity, which has been correlated with pharmaceutical activity for treating eating disorders, such as obesity and hyperphagia, and diabetes.
The compounds of formula I display pharmacological activity in a test procedure designed to demonstrate MCH receptor antagonist activity. The compounds are non-toxic at pharmaceutically therapeutic doses. Following is a description of the test procedure.
MCH Receptor Binding Assay
Membranes from CHO cells expressing the MCH receptor were prepared by lysing cells with 5 mM HEPES for 15 min at 4 C. Cell lysates were centrifuged (12.5000xc3x97g, 15 min) and the pellet was resuspended in 5 mM HEPES. For each 96-well plate (Microlite, Dynex Technologies), 1 mg of cell membranes were incubated with 10 mg of wheat germ agglutinin SPA beads (Amersham) for 5 min at 4 C in a volume of 10 ml of binding buffer (25 mM HEPES, 10 mM MGCl2, 10 mM NaCl, 5 mM MnCl2, 0.1% BSA). The membrane/bead mixture was centrifuged (1500xc3x97g, 3.5 min), the supernatant was aspirated, and the pellet was resuspended in 10 ml binding buffer. The centrifugation, aspiration and resuspension were then repeated. The membrane/bead mixture (100 l) was then added to 96-well plates containing 50 l of 500 pM [125I]-MCH (NEN) and 50 ml of the appropriate concentration of compound (4xc3x97 the desired final concentration). Nonspecific binding was determined by including 1 M MCH in the binding reaction. The binding reaction was incubated at room temperature for 2 h. Plates were then analyzed in a TOPCOUNT microplate scintillation counter (Packard). Data was analyzed and Ki values were determined using GraphPad Prim.
For the compounds of this invention, a range of MCH receptor binding activity (Ki values) of from about 3 nM to about 1500 nM was observed. Compounds of this invention preferably have a binding activity in the range of from about 3 nM to about 500 nM, more preferably from about 3 to about 200 nM, and most preferably from about 3 to about 80 nM.
For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington""s Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.
Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
Preferably the compound is administered orally.
Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application.
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 300 mg/day, preferably 1 mg/day to 50 mg/day, in two to four divided doses.